Environmental toxicants including pesticides may contribute to the development of various neurodegenerative disorders including Parkinson's disease (PD). One of the mechanisms implicated in various neurodegeneration is neuronal apoptosis. We discovered that chlorpyrifos and rotenone both stimulate apoptosis in neuronal cells, suggesting that pesticide-induced apoptosis may play a role in neurodegeneration. Consequently, it is important to elucidate molecular mechanisms for induction of apoptosis by pesticides in neurons. The overall objective of this project is to elucidate apoptotic mechanisms for chlorpyrifos- and rotenone-induced apoptosis in neurons. Chlorpyrifos, an organophosphate pesticide, is one of the most commonly used pesticides. Its primary target of toxicity is the CNS. Treatment of rats with rotenone, a common insecticide, causes all PD symptoms. Therefore, chlorpyrifos and rotenone, two distinct classes of pesticides, are chosen as models to study pesticide-induced neuronal apoptosis. Our preliminary data suggest that both chlorpyrifos and rotenone induce apoptosis in primary cultured cortical neurons and SH-SY5Y cells. They also activate the stress-activated MAP kinases, JNK and p38. We hypothesize that activation of these kinases is important for chlorpyrifos- and rotenone-induced apoptosis in neurons. We will test this hypothesis and elucidate downstream mechanisms by which chlorpyrifos and rotenone stimulation of JNK and p38 causes neuronal apoptosis. This study should provide valuable new information concerning the molecular basis of pesticide-induced apoptosis in neurons and new insights concerning the role of environmental toxicants in neurodegeneration.